NM_003000.3(SDHB):c.137G>A (p.Arg46Gln) AND Paragangliomas 4

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jun 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000232432.12

Allele description [Variation Report for NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)]

NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)

Gene:

SDHB:succinate dehydrogenase complex iron sulfur subunit B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.13

Genomic location:

Preferred name:

NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)

Other names:

p.R46Q:CGA>CAA

HGVS:

NC_000001.11:g.17044824C>T
NG_012340.1:g.14347G>A
NM_003000.3:c.137G>AMANE SELECT
NP_002991.2:p.Arg46Gln
NP_002991.2:p.Arg46Gln
LRG_316t1:c.137G>A
LRG_316:g.14347G>A
LRG_316p1:p.Arg46Gln
NC_000001.10:g.17371319C>T
NM_003000.2:c.137G>A
P21912:p.Arg46Gln
p.R46Q

Protein change:

R46Q

Links:

UniProtKB: P21912#VAR_054377; dbSNP: rs772551056

NCBI 1000 Genomes Browser:

rs772551056

Molecular consequence:

NM_003000.3:c.137G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Paragangliomas 4 (PPGL4)
Synonyms:: CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS; Pheochromocytoma, extraadrenal and cervical paraganglioma; Paragangliomas, hereditary extraadrenal; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007273; MedGen: C1861848; Orphanet: 29072; OMIM: 115310

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000677773	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Feb 2, 2017)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16317055, 26719882, 18840642, 22835832, 24659481, 23175444, 25972245, 23512077 Citation Link,
SCV000782272	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000993583	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI_GT	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 9, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV004045422	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Apr 24, 2023)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22677546, 26719882, 25972245, 12618761, 28374168, 23512077, 34439168 Citation Link,
SCV004362282	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 1, 2023)	germline	clinical testing	PubMed (27) [See all records that cite these PMIDs] 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 22835832, 23175444, 23512077, 24102379, 24606901, 24659481, 25972245, 26719882, 28374168, 28503760, 28738844, 29386252, 29951630, 31492822, 32741965, 32963463, 34439168, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	1	not provided	not provided	1	not provided	clinical testing, research

Citations

PubMed

Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors.

Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, Zhao S, Ye D, Xiong Y, Guan KL.

Genes Dev. 2012 Jun 15;26(12):1326-38. doi: 10.1101/gad.191056.112. Epub 2012 Jun 7. Erratum in: Genes Dev. 2015 Apr 15;29(8):887..

PubMed [citation]

PMID:: 22677546
PMCID:: PMC3387660

Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma.

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rötig A, Jeunemaitre X.

J Clin Endocrinol Metab. 2002 Oct;87(10):4771-4.

PubMed [citation]

PMID:: 12364472

See all PubMed Citations (28)

Details of each submission

From Counsyl, SCV000677773.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782272.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI_GT, SCV000993583.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004045422.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22677546, 26719882, 25972245]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12618761, 28374168, 23512077, 34439168].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV004362282.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (27)

Description

This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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